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© Marie Prévost, Institut Pasteur
Image of a portion of a Xenopus oocyte expressing a channel receptor.
Publication : Nature communications

The desensitization pathway of GABAA receptors, one subunit at a time.

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Nature communications - 23 Oct 2020

Gielen M, Barilone N, Corringer PJ,

Link to Pubmed [PMID] – 33097732

Link to DOI [DOI] – 10.1038/s41467-020-19218-6

Nat Commun 2020 10; 11(1): 5369

GABAA receptors mediate most inhibitory synaptic transmission in the brain of vertebrates. Following GABA binding and fast activation, these receptors undergo a slower desensitization, the conformational pathway of which remains largely elusive. To explore the mechanism of desensitization, we used concatemeric α1β2γ2 GABAA receptors to selectively introduce gain-of-desensitization mutations one subunit at a time. A library of twenty-six mutant combinations was generated and their bi-exponential macroscopic desensitization rates measured. Introducing mutations at the different subunits shows a strongly asymmetric pattern with a key contribution of the γ2 subunit, and combining mutations results in marked synergistic effects indicating a non-concerted mechanism. Kinetic modelling indeed suggests a pathway where subunits move independently, the desensitization of two subunits being required to occlude the pore. Our work thus hints towards a very diverse and labile conformational landscape during desensitization, with potential implications in physiology and pharmacology.

https://pubmed.ncbi.nlm.nih.gov/33097732